FINAL PROGRAM

CASSS Bay Area Discussion Group

Co-chairs: Vinaya Kapoor, Johnson & Johnson (Janssen R & D) Min Young, Ultragenyx Pharmaceutical

South San Francisco Conference Center South San Francisco, CA June 9, 2016

Table of Contents

Conference Program Partners…………………………………………………………….…….3

Acknowledgements……………………………………………………………………………..4

General Information…………………………………………………………………………….5

Scientific Program Summary……………………………………………………………...……6

Program and Speaker Abstracts………………………………………………………………...7

Roundtable Discussion Point Sheets……………………………………………………………9

Note Paper……………………………………………………………………………………..19

The Organizing Committee gratefully acknowledges the Conference Program Partners for their generous support of this Bay Area Discussion Group workshop

Program Partners

Agilent Technologies

Boehringer Ingelheim

Genentech, a Member of the Roche Group

Acknowledgements

Special Thanks to all of the Program Committee Members who helped develop this Bay Area Discussion Group Workshop Program Committee Kris Antonsen, BioMarin Pharmaceutical, Inc. Dawn Benson, Coherus Min Chen, Ultragenyx Pharmaceutical Judy Chou, Medivation Kathy Francissen, , a Member of the Roche Group Malou Gemeniano, Boehringer Ingelheim Vinaya Kapoor, Johnson & Johnson (Janssen R & D) David Passmore, Bristol-Meyers Squibb Company Aran Paulus, Thermo Fisher Scientific Joanne Severs, Bayer Lance Wong, Strand Bio DBA Christopher Yu, Genentech, a Member of the Roche Group Eike Zimmermann, Boehringer Ingelheim

Roundtable Facilitators Dawn Benson, Coherus Adam Catherman, Genentech, a Member of the Roche Group Susan Chen, Boehringer Ingelheim Natalie Ciaccio, BioMarin Pharmaceutical, Inc. Guifeng Jiang, Boehringer Ingelheim Julian Kissmann, Boehringer Ingelheim Srikanth Kotapati, Bristol-Myers Squibb Weijun Li, Bayer Ying Liu, Johnson & Johnson (Janssen R & D) Rob McCombie, Genentech, a Member of the Roche Group Yanli Mi, Gilead Steven Rabin, Johnson & Johnson (Janssen R & D) Nicole Samuels, Bayer Jennifer Thompson, Agilent Technologies

Audio Visual: Michael Johnstone, MJ Audio-Visual Productions CASSS Staff Stephanie L. Flores, CAE, Executive Director Anna Lingel, Registration Manager Linda Mansouria, CMP, CMM, Conference Manager

General Information

Name Badges Please wear your name badge throughout the day.

Registration The registration desk will be open from 8:00 a.m. to 3:30 p.m. We will accept walk-in registrations. Registration is located in the Baden A & B Foyer at the South San Francisco Conference Center.

Roundtable Session There are 7 roundtable topics for you to determine which table topic you would like to be part of the discussion. The 7 table topics are:

Table Topic 1: Don’t Get in a Bind Over Specifications

Table Topic 2: Leveraging Platform Information Appropriately

Table Topic 3: S-T-A-B-I-L-I-T-Y – You Ain’t Got No Alibi: Stability Strategies for Phase I and Beyond

Table Topic 4: Structural Characterization

Table Topic 5: Global Filing Challenges

Table Topic 6: To Infinity and Beyond – Analytical Method Development

Table Topic 7: Working with Contract Manufacturers

Tables are set with 14 seats to a table. Table topics are on a first come, first serve basis. These roundtables will include two facilitators, whose role is to help assist the discussion and ensure a lively exchange, and a scribe, whose role is to make general, anonymous notes about the discussion so others can have a change to view the discussion even if they could not participate. The discussion notes will be shared with all attendees during the summary period of the program.

Wi-Fi Access The South San Francisco Conference Center has complimentary Wi-Fi Access. Log into SSFCC- Free Wi-Fi network.

Scientific Program Summary

THURSDAY, JUNE 9, 2016 08:00 – 15:30 Registration in the Baden Room Foyer 08:00 – 09:00 Continental Breakfast in Salons B-D

09:00 – 09:30 CASSS Welcome and Introductory Comments Kathleen Francissen, Genentech, a Member of the Roche Group

09:30 – 10:15 Building A Quality Dossier Howard Anderson, CDER, FDA

10:15 – 11:00 Let’s Start at the Very Beginning, a Very Good Place to Start! Building and Maintaining a Quality CMC Dossier Michelle Frazier, AbbVie, Inc.

11:00 – 11:30 AM Break in Salons B - D

11:30– 12:15 Panel Discussion Facilitated by: Vinaya Kapoor, Johnson & Johnson (Janssen R & D)

Panel Members: Howard Anderson, CDER, FDA Michael Boyne, BioTech Logic Michelle Frazier, AbbVie, Inc. Malou Gemeniano, Boehringer Ingelheim Lisa Regan, Bayer

12:15 – 13:15 Networking Lunch in Salons B-D

13:15 – 14:00 Roundtable Discussions in Baden Room

14:00 – 14:15 PM Break and Roundtable Summaries Created in the Baden Room

14:15 – 15:15 Summary of Roundtable Discussions by Table Facilitators

15:15 – 15:30 Closing Remarks Judy Chou, Medivation, and Lance Wong, Strand Bio DBA

Program Abstract

Building a “Quality” Dossier from Phase 1 and Beyond Development of a “Quality” Dossier containing the appropriate level of Chemistry, Manufacturing and Control information is an integral element of global regulatory submissions to support clinical development programs. First and foremost, regulations and guidance must be considered as the dossier is being prepared. Additionally, the phase of development, molecule complexity, and available molecule knowledge are key elements to consider when developing the dossier content. This meeting will provide an interactive forum for individuals from academia, industry and the FDA to come together to discuss the challenges and best practices for preparing a phase appropriate “Quality” Dossier. Key discussion topics will include, establishing specifications, analytical method development, structural characterization, stability approaches, and leveraging platform information when preparing dossiers to support global clinical programs. The meeting format is designed to provide attendees the opportunity to hear current perspectives from the FDA and Industry and to network through participation in facilitated small group discussions.

Speaker Abstracts

An FDA Reviewer’s View on Building a Quality Dossier Howard Anderson, CDER/OPQ/OBP, FDA The number of FDA approved original Biological License Applications (BLA) for monoclonal antibody and therapeutic protein products is growing at an accelerated rate. In 2015, CDER approved 45 novel new drug therapies. Twelve of which are BLA products. Product quality submissions to regulatory authorities are a critical component for successful drug development. This presentation will provide a FDA product reviewer’s perspective on building a quality dossier from the pIND meeting through filling BLA supplements for product life cycle management. Focused quality regulatory submissions make FDA sponsor meeting more productive, facilitate application review, and best utilize FDA resources for application decisions. In contrast a deficient submission may delay the product development program. The goal for all stake holders is to facilitate the rapid clinical development and approval of high quality for patients. Case studies will be provided for monoclonal antibody and therapeutic protein products regulated by the Office of Products (OBP) at CDER. The case studies will illustrate lessons learned and best practices for providing adequate information to the FDA at the various stages of product development. The examples involve analytical method development, product characterization, justifying specifications, and stability commitments. Let’s Start at the Very Beginning, a Very Good Place to Start! Building and Maintaining a Quality CMC Dossier Michelle Frazier, AbbVie Inc. High quality submissions are essential for the success of any development program from pre-first in human (FIH) through post-licensure, whether they are meeting packages or Module 3 quality sections in support of a application or a marketing application. In contrast, submissions that are not focused and do not contain the appropriate level of detail or data can have a negative outcome for a given clinical program. This presentation will outline Industry best practices and lessons learned in building quality regulatory submissions throughout the product lifecycle.

Roundtable Discussion Points

TABLE 1 TOPIC: Don’t Get in a Bind over Specifications – Setting Appropriate Specifications FACILITATORS: Ying Liu, Johnson & Johnson (Janssen R & D) Yanli Mi, Gilead

SCRIBE: Kris Antonsen, BioMarin Pharmaceutical, Inc.

SCOPE: Setting realistic specifications for analytical analyses is an exercise that almost every company conducts routinely. However, the strategies and practices could be diverse. We will discuss strategies for setting specifications and what to consider when setting specifications.

BULLET POINTS FOR DISCUSSION: Are quantitative specifications required or is “report results” sufficient? a. When is “Report Results” acceptable for early-phase products? What analyses (appearance, ID, assay, impurities/degradation products, counterion potency, etc.)? b. Should “Report Results” be used alone or should a “Target” be listed as well? c. DS versus DP? Does this matter? 2. What is the focus for setting specifications for early-phase products? Patient safety, efficacy, etc? a. Typically, early-phase products focus on patient safety first and foremost. Is this the correct approach? What else should be focused on for early-phase products? b. What other attributes with regards to specifications should be focused on as the product moves throughout its lifecycle? 3. Control strategy for setting specifications a. Where does information come from for final drug product specifications? (IP testing, FP testing, stability testing, etc.)? b. Is monitoring IP testing results helpful in setting of specifications? c. How does this process evolve from early-phase to late-phase products? d. What roles do manufacturing history and clinical relevance play in specification setting? e. How are preclinical data used to set specs? f. Who is the final decision-maker after the cross-functional process?

4. Other topics a. What is the range of regulatory feedback that companies have received, e.g., relative to specification tightening? d. Once the cross-functional process of proposing specs has taken place internally, who is the final decision-maker?

TABLE 2 TOPIC: Leveraging Platform Information Appropriately FACILITATORS: Weijun Li, Bayer Adam Catherman, Genentech, A member of the Roche Group

SCRIBE: Judy Chou, Medivation SCOPE: The pharmaceutical industry has accumulated a large body of platform knowledge in process development. Many organizations have been successfully leveraging their technology platforms to streamline process development activities. However, companies continue to face challenges on how to leverage platform information in the dossier to support successful global submissions. This round table discussion will focus on these issues through open discussion of current strategies.

BULLET POINTS FOR DISCUSSION: 1) What are the considerations for establishing a platform data set? a. What is the definition of “platform data set”? b. Do they vary based on the phase of development (IND vs BLA?) c. How much data and / or how many molecules are needed to be considered a platform? How is the platform process verified? d. What are the considerations to account for the target molecule profile? e. What is the eligibility of next-in-class-molecule to leverage platform process? 2) What are examples of successful of incorporation of platform information into the dossier (e.g. Viral Clearance and Method Validation)? 3) How is platform information incorporated into the CMC Dossier? a. What has worked well? b. What are the challenges? c. How is platform information maintained when additional information is obtained for the platform 4) Is the use of platform information in a dossier globally accepted? What are the challenges globally?

TABLE 3 TOPIC: S-T-A-B-I-L-I-T-Y - You Ain’t Got No Alibi: Stability Strategies for Phase I and Beyond FACILITATORS: Natalie Ciaccio, BioMarin Pharmaceuticals, Inc. Srikanth Kotapati,

SCRIBE: JoAnn Severs, Bayer

SCOPE: This table will discuss stability strategies applied to Phase I through the Marketing Application for Biologics. Table members will provide areas of challenge and success for clinical trials and marketing applications with a global perspective in mind. Participants will consider the use of unique strategies as well as stability modeling and extrapolation to support shelf-life. BULLET POINTS FOR DISCUSSION: 1. What unique or different stability strategies have you used for transitioning from supportive stability work using development or pilot scale material to Phase I and how did those progress to later phases? For example, matrixing and bracketing approaches? 2. What is your strategy for placing material on stability with respect to the launch manufacturing site? If not from the commercial site, what is your strategy for bridging? 3. How do you manage in-use stability studies to support clinical use as well as to support the marketing application? 4. What strategies and methods have you used for shipping stability evaluation? 5. Have you used modelling to support product shelf life in lieu of full stability data? How successful have you been gaining regulatory approval? What types of challenges have you faced? 6. What regulatory challenges have you faced for stability with respect to agency questions globally?

TABLE 4 TOPIC: Structural Characterization FACILITATORS: Guifeng Jiang, Boehringer-Ingelheim Nicole Samuels, Bayer

SCRIBE: Christopher Yu, Genentech, a Member of the Roche Group

SCOPE: This table will discuss characterization strategies for early phase development candidates. Table members will provide examples of best practices as well as experiences with regulators. BULLET POINTS FOR DISCUSSION: 1. Risk-based approach for determining the level of structural characterization needed to support early phase candidates – how much is enough and how much is too much? 2. What to include in a Ph1 IND and where in the CTD? a. Where does Ref std characterization data go? 3. What guidance information is available from regulatory bodies? 4. Which samples are used for characterization? a. Which analyses for DS, DP, and ref std? 5. Which analytical techniques are used for structural characterization? Emerging technologies on structure characterization? 6. What level of method assessment is needed for structural characterization analytical methods? 7. Biosimilars a. Structural characterization to support comparability studies? b. When true side by side testing is required? c. Setting acceptance criteria for comparability?

TABLE 5 TOPIC: Global Filing Challenges FACILITATORS: Dawn Benson, Coherus Rob McCombie, Genentech, a Member of the Roche Group

SCRIBE: Min Chen, Ultragenyx Pharmaceutical

SCOPE: The understanding, the strategies, and the practices for global filings could vary greatly from company to company. We will seek to define the terms of “global” and “filings” first to set the tone for today’s discussion. PREFACE: Facilitators to introduce topic and define ‘global’ for the group to frame terms of the discussion – EU, US, ICH-regions and RoW/non-ICH countries Facilitators will ask group to introduce themselves, including work focus and clinical phase of interest and experience Facilitators will then decide on lifecycle phase to focus discussion on – clinical, or marketing application / registration – (let the roundtable decide from quick poll) Facilitators will introduce points for discussion below and let group decide which to focus (e.g. that overall strategy is discussed, then pick 1 to 2 other topics, time dependent)

BULLET POINTS FOR DISCUSSION: Strategy Point What is the breadth of experience at the table regarding global strategy development?

 Are target markets identified and developed well in advance of initial filing, and therefore inform the CMC strategy up front (country requirements may, for example, impact process validation, stability, transport validation)?  Is a single core market developed and authored for in first instance, e.g. US/EU, both and other regions / countries considered after major market approval?  For US/EU is simultaneous submission sought and/or achieved?  How are additional countries managed, if added late to the list, but a priority from a commercial perspective?  Where do you obtain country specific intelligence from? internal/prior experience/affiliates/CROs/Health Authority published guidance/regulation?

Discussion points for team to select from

1. Can the same CMC content / level of detail be used in all geographies? a. “One size fits all” dossier

How is this dossier authored? o A global dossier that is authored as complete for all countries and redacted to fit each? o Authored for one major market and adapted as needed for others?  Does this approach vary with company size?  How are partner companies managed if/when they manage other territories, but you are responsible for CMC content/dossier authoring?  How are Intellectual Property issues taken account during authoring? o Does IP lack of protection / concerns in a country ever trump country guidance/requirements? o Who has the final decision? Technical functions or legal?

2. Managing content (e.g., keeping track of what is filed where)

 How are dossier sections versioned upon health authority required changes during review? o Are other countries sections updated inline, if permissible by local law)?  How is content of sections controlled or tracked with versioning to allow ease of future change control?  CPP/CMP reference countries issues, where applicable (level of detail and supply chain issues)

3. Strategies for responding to questions a. Making & tracking commitments (see above for tracking content) 4. Managing changes across geographies (e.g., manufacturing process, specifications, …)

 How are the divergent times to approval managed? o e.g. site / process changes (launch site for US/EU, often different to commercial mature demand site/process/scale? New site may approve in US/EU before RoW approvals of initial facility / process / scale- how do companies manage this – wait for new site or manage complicated inventory and manufacturing schedule?  Supply chain restrictions e.g. single source of DP and/or DS manufacture (can result in comparability, validation and / or stability complications)

5. Handling divergence across geographies (e.g., specifications, expiry dating, …)

 Is product released to the tightest internal specification globally or to individual country approved specification?

6. Interpreting local regulatory guidance/law/advice (where it exists…)

 Who / on which organization do you rely on for reliable country specific advice?

7. Changing local regulatory advice

 How do you/ have you coped with changing local regulation during review of MA?

8. GMP related issues

o e.g. Pre-approval inspection, bespoke GMP dossier, PAI scheduling - especially if limited batches are to be performed

9. ICH Q guidance applicability in non-ICH regions post-approval (e.g. Brazil, Mexico, Turkey, Russia, India, China, South Korea)

 Do you have experience where ICH guidance has not been accepted? o (e.g. stability, quality risk management, validation, country specific pharmacopeia, comparability)  File CTA then file MAA in emerging markets, pressure test quality dossier.

10. Does company size / international experience and/or working with a CMO / CRO / partner/ affiliates impact any of these points, e.g. the strategy a company used globally

TABLE 6 TOPIC: To Infinity and Beyond – Analytical Method Development FACILITATORS: Vikas Bhat, BioMarin Pharmaceuticals Susan Chen, Boehringer-Ingelheim

SCRIBE: Eike Zimmermann, Boehringer-Ingelheim SCOPE: Analytical method development can be a balancing act during the early stages of a product’s development. Companies continue to struggle with defining the ideal timing and scope for method development, qualification, and validation, as well as deciding what data is appropriate to include in a submission. This table will focus on these issues through open discussion of current strategies.

BULLET POINTS FOR DISCUSSION:

1. Too much testing early on vs. too little lot data – what is just right for a Phase 1 submission? 2. When does a characterization method become routine testing? 3. Qualification vs. validation – what’s appropriate for early stage development? 4. Setting appropriate system suitability criteria at different phases – balancing failures and investigations against the risk of data variability 5. Challenges associated with high throughput screening (for example, microfluid technology) 6. Critical quality attributes – do common method sets drive criticality assessments or do quality attributes determine the need for methods?

TABLE 7

TOPIC: Working with Contract Manufacturers FACILITATORS: Julian Kissmann, Boehringer-Ingelheim Steven Rabin, Johnson & Johnson (Janssen R & D)

SCRIBE: David Passmore, Bristol-Myers Squibb SCOPE: This table will discuss how to get the most out of a relationship with a CMO partner.

BULLET POINTS FOR DISCUSSION:  The CMO employee profile may appear to be similar to that of an innovator company, but the business model is completely different. Therefore: o Conducting process development at a CMO can be difficult. Milestones for this may not be as concrete as for manufacture of DS/DP. o Maintaining release testing timelines can be difficult.  Plan ahead: there is an industry wide shortage of capacity – therefore it can be difficult to find production slots at the CMO.  Innovator’s QC criteria must be aligned with the contract site—must be very specific regarding release criteria.  Contract site may be physically located far away—time and cultural differences may be an issue.  Be wary of scope creep—asking for things outside the original contract can lead to severe project delays and increased costs.  You are buying the CMO’s quality system as well as their ability to manufacture. Make sure it is consistent with your own.  No matter what the CMO does, the contracting company (innovator) is still responsible for the final product.  As a customer, it is important to understand the requirements that you will put on the CMO upfront…from the Regulatory perspective, this includes getting relevant documentation for all country filings, some of which are very onerous.  Tip for innovators: treat the CMO like partners. They appreciate it and will go the extra mile for you when needed. If you treat them like hired hands, they will respond accordingly.  The CMO Project Manager is the primary contact for the external partner and can/should be your best ally.  Transfer of analytics can be difficult to do well, but it can be critical for release and in- process control. Any detail not fully discussed and verified is at risk.  A list of ‘Preferred CMOs’ is often maintained at innovator companies – a database approach could help to catalog and avoid bad experiences.

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